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Lipoxygenase-dependent superoxide release in skeletal muscle

¹Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, and ²Department of Anesthesiology, The Ohio State University, Columbus, Ohio 43210

Submitted 2 February 2004 ; accepted in final form 2 April 2004

Superoxide anion radical (O₂^–) is released from skeletal muscle at rest and is particularly elevated during conditions of heat stress (42°C). Previous studies have shown that in isolated rat diaphragm O₂^– release is not dependent on mitochondrial electron transport, reduced NADP oxidase activity, or the integrity of membrane anion channels. This study hypothesized that O₂^– release, as measured by cytochrome c reduction, is linked to metabolism of arachidonic acid. Phospholipase A₂ inhibition with manoalide significantly decreased O₂^– release. In downstream pathways, neither the blockage of cyclooxygenase with indomethacin nor the inhibition of cytochrome P-450-dependent monooxygenase with SKF-525A decreased O₂^– release. However, lipoxygenase (LOX) inhibition with general LOX blockers 5,8,11,14-eicosatetraynoic acid and cinnamyl-3,4-dihydroxy--cyanocinnamate greatly attenuated the signal. Furthermore, the specific 5-LOX inhibitor diethylcarbamazine also significantly decreased O₂^– release. Immunohistochemistry localized 5- and 12-LOX to the cytosol and sarcolemma of muscle cells. Confocal studies, using the O₂^–-sensitive fluorescent indicator hydroethidine, demonstrated that LOX inhibition had no significant influence on intracellular O₂^– formation. When compared with the cytochrome c results, this indicates that intra- and extracellular O₂^– must arise from different sources. These data show for the first time that arachidonic acid metabolism through LOX activity, is a major source of extracellular O₂^– release in skeletal muscle.

manoalide; hydroethidine; arachidonic acid; cytochrome c; heat stress

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